Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis

Zhe Jin, Yuriko Mori, James P. Hamilton, Alexandru Olaru, Fumiaki Sato, Jian Yang, Tetsuo Ito, Takatsugu Kan, Rachana Agarwal, Stephen J. Meltzer

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND. The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis. METHODS. SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2′-deoxycytidine (5-Aza-dC). RESULTS. SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05). CONCLUSIONS. SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus.

Original languageEnglish (US)
Pages (from-to)43-49
Number of pages7
JournalCancer
Volume112
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Barrett esophagus
  • Esophageal adenocarcinoma
  • Esophageal squamous cell carcinoma
  • Hypermethylation
  • Somatostatin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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